The invention relates to a contraceptive composition of a prolactin elevating benzamide, such as sulpiride or N-[(1-ethyl-2-pyrrolidinyl) methyl]2-methoxy 5-sulfamoyl benzamide, and a progestogen.
Benzamides, such as sulpiride, are primarily known for their psychotropic properties. Sulpiride was observed to have a contraceptive effect at the usual doses employed to treat patients for psychiatric disorders, (100 to 1000 mg per day). It has not been used extensively as a contraceptive, however, because of the relatively high dosage required for satisfactory protection and because clinical tests have shown that protection is incomplete during the first two months of drug administration. (D. Buvat et al. Rev. Fr. Gynecol. Obstet. 71 (1) pp. 53-51).
The use of psychotropic substances for contraceptive purposes has previously been recommended only in the form of local application as illustrated, for example in PCT publication Nos. 81/03421 and 83/00086 issued to Cormier, which describe preparations for intra-vaginal or intra-uterine use. These preparations include a psychotropic derivative, such as a phenothiazine or benzodiazepine, which is employed as a foam, jelly, or other conventional pharmaceutical vehicle for external use. In principle, the usual spermicidal compound is combined with or replaced by a psychotropic substance, which penetrates the spermatozoon membrane and inhibits spermatozoon activation by calmoduline, thus blocking the spermatozoon's fertilizing action.
It is known to use progestogens for contraceptive purposes. A distinction is made between three types of contraceptive use:
(1) Daily use at very low doses
At low doses, progestogens modify the cervical mucus and thus prevent spermatozoa from entering the cervix. Use of progestogens at these doses, however, also interferes with gonadotrophin secretion (FSH and LH), giving rise to the following therapeutic disadvantages:
incomplete contraceptive effect, particularly at the beginning of treatment; PA1 intermittent break-through bleeding; and PA1 suppression of withdrawal bleeding, obtained with intermittently administered treatment required to preserve the psychological comfort of recurring "menstrual" cycles. Norgestrel used at a rate of 30 micrograms per day or norethindrone used at a rate of 300 micrograms per day are typical examples of daily low-dose progestagen therapy. PA1 disappearance of the "menstrual" cycle; PA1 irregular or prolonged bleeding; and PA1 uncertainty with respect to the time at which fertility is restored after treatment is discontinued.
(2) Use for 21 days per cycle at high doses
The contraceptive effect achieved by progestogens administered according to this treatment schedule results from inhibition of gonadrotrophin secretion, as, for example, with 2 mg of ethynodiol diacetate daily for 21 days. Such treatment has disadvantages and may induce severe endometrial atrophy, with remitting metrorrhagia or absence of "menstruation" between courses of treatment. In addition, the clinical tolerance of this method is judged to be too highly uncertain.
(3) Use in "depot" form
Contraception is achieved by monthly injections of medroxyprogesterone acetate (known for example under the trade name DEPO-PROVERA). Progesterone administered in this way presents the following disadvantages which are non-reversible as long as the effect of the injection persists:
It is also well known that a number of contraceptive preparations combine a progestogen and an estrogen generally ethinyl-estradiol). The estrogens contained in such combinations, however, are considered to cause certain metabolic disturbances and hepatic or thrombo-embolic accidents. Consequently, this type of contraception is not feasible in all situations due to the risks of estrogen therapy or its contra-indication in certain patients.